Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling.
Silibinin Treatment Inhibits the Growth of Hedgehog Inhibitor-Resistant Basal Cell Carcinoma Cells via Targeting EGFR-MAPK-Akt and Hedgehog Signaling.
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DOI：
10.1111/php.12727
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发表时间：
2017-07
影响因子：
3.3
通讯作者：
Agarwal R
中科院分区：
文献类型：
--
作者：
Dheeraj A;Rigby CM;O'Bryant CL;Agarwal C;Singh RP;Deep G;Agarwal R
Basal cell carcinoma (BCC) is the most common skin malignancy. Deregulated hedgehog signaling plays a central role in BCC development; therefore hedgehog inhibitors have been approved to treat locally advanced or metastatic BCC. However, the development of resistance to hedgehog inhibitors is the major challenge in effective treatment of this disease. Herein, we evaluated the efficacy of a natural agent silibinin to overcome resistance with hedgehog inhibitors (Sant-1 and GDC-0449) in BCC cells. Silibinin (25–100 μM) treatment for 48 hrs strongly inhibited growth and induced death in ASZ001, Sant-1 resistant (ASZ001-Sant-1) and GDC-0449 resistant (ASZ001-GDC-0449) BCC cells. Furthermore, colony forming ability of ASZ001, ASZ001-Sant-1 and ASZ001-GDC-0449 cells was completely inhibited by silibinin treatment. Molecular analysis showed that silibinin treatment decreased the level of phosphorylated-EGFR (Tyrosine-1173) and total EGFR in ASZ001-Sant-1 cells; key signaling molecules responsible for BCC resistance towards hedgehog inhibitors. Further, silibinin treatment decreased the phosphorylated-Akt (Serine-473), phosphorylated-ERK1/2 (Threonine 202/Tyrosine 204), cyclin D1 and Gli-1 level but increased the SUFU expression in ASZ001-Sant-1 resistant cells. Silibinin treatment of ASZ001-Sant-1 resistant cells also decreased bcl-2 but increased cleaved caspases 3 and PARP cleavage, suggesting induction of apoptosis. Together, these results support silibinin use to target hedgehog inhibitors resistant BCC cells. In the present study, we evaluated the efficacy of a natural agent silibinin to overcome resistance against hedgehog inhibitors (Sant-1 or GDC-0449) in basal cell carcinoma (BCC) cells. The silibinin treatment strongly inhibited the cell growth and induced death in ASZ001, ASZ001-Sant-1 resistant and ASZ001-GDC-0449 resistant BCC cells. Colony forming ability of the hedgehog inhibitor resistant BCC cells was completely inhibited with silibinin treatment. Mechanistic studies revealed that silibinin inhibits EGFR-MAPK-Akt and hedgehog signaling in resistant BCC cells. Silibinin treatment also targeted the key cell death associated molecules in the resistant BCC cells.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.5
作者：
Axelson, Michael;Liu, Ke;Pazdur, Richard
通讯作者：
Pazdur, Richard
DOI：
10.1038/nrc2503
发表时间：
2008-10
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.8
作者：
Gu, M;Dhanalakshmi, S;Agarwal, R
通讯作者：
Agarwal, R
影响因子：
82.9
作者：
Fan, HR;Oro, AE;Khavari, PA
通讯作者：
Khavari, PA